Acute lymphoblastic leukemia (ALL) is a neoplasm of immature lymphoid progenitors that is most commonly of B cell lineage. B-precursor acute lymphoblastic leukemia (B-ALL) is the most common childhood malignancy and the number one cause of cancer-related mortality in children and young adults; see Mullighan, J Clin Invest. 122(10):3407-3415 (2012); Hoelzer and Gale, Semin Hematol 24 (1): 27-39 (1987). The vast majority of cases of B-ALL are associated with aneuploidy or gross chromosomal rearrangement.
B cell differentiation is characterized by stage-specific expression of cell surface markers and recombination of the immunoglobulin heavy chain (IgH) and light chain (IgL) genes. These events are responsible for the generation of a large pool of immature B cells from which selection based on antigen receptor specificity takes place1,2. Productive rearrangements at the Igh locus allow pairing of the expressed IgM with the surrogate light chains (SLC), VpreB and λ5, and the proximal signaling molecules Igα and Igβ to form a pre-B Cell Receptor (pre-BCR) signaling complex. Subsequent engagement of the protein tyrosine kinases (PTKs) Lyn, Fyn, Blk and Syk activates signaling cascades supporting pre-B cell proliferative expansion and differentiation3. Loss-of-function mutations in the pre-BCR signaling complex or in associated PTKs cause arrest at an early B cell precursor stage4-10. The pre-BCR, working in concert with the growth-promoting IL-7 cytokine receptor (IL-7R), activates the PI3K-Akt and Mitogen-Activated protein kinases (MAPK) Erk1 and Erk2, thereby providing pre-B cell survival and proliferation11-14.
Pre-BCR signaling also induces differentiation through a distinct set of signaling effectors such as Btk, Slp65 (Blnk) and PLCγ2 (refs. 15-17). These inhibit the PI3K pathway while activating Ca2+ signaling and a network of transcription factors responsible for cell cycle withdrawal and immunoglobulin light chain (IgL) gene rearrangement18-20. Although the importance of pre-BCR signaling in proliferation and differentiation is well established, how the transition between these two disparate phases occurs remains unclear. Loss in IL-7R signaling as well as quantitative and qualitative changes in pre-BCR signaling have been proposed as possible mechanisms underlying this pre-B cell switch.